Hospital Medicine

Crohn's Disease

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Crohn’s disease, also known as regional enteritis, is an idiopathic, inflammatory disorder primarily affecting the small intestine with large intestine involvement in 50-70% of patients. It is a systemic disorder that may have several extraintestinal manifestations. One of two distinct entities known to cause inflammatory bowel disease, Crohn’s disease features transmural inflammation resulting from an imbalance between inflammatory mediators in the gut to intestinal microbes in a genetically susceptible host.

The pathophysiology of Crohn’s has been extensively studied, yet there still exists much uncertainty about the underlying cause and reason for certain populations being affected more than others. The central mechanism of the disease is T cell activation against microbial antigens leading to cytokine release and inflammatory tissue injury. This inflammatory damage can manifest in many different ways, from superficial ulceration to deep transmural damage. In the more severe forms, the transmural damage is associated with the formation of pathognomonic non-caseating granulomas and can be complicated by stricture and fistula formation. Chronically, Crohn’s is associated with crypt abscess formation and villous blunting.

The etiology for Crohn’s disease is likely multifactorial as genetic, microbial, environmental, and host factors have been associated with disease.

The diagnosis of Crohn’s can be challenging as many of the history and physical exam features are nonspecific and difficult to characterize. Definitive diagnosis usually involves colonoscopic biopsy, although the typical pathologic findings of granulomas on biopsy can often have a low yield.

Common complaints associated with Crohn’s disease are abdominal pain, diarrhea, fever, and rectal bleeding. Depending on duration of symptoms, these can also be accompanied by nausea, anorexia and weight loss.

Once the diagnosis of inflammatory bowel disease is suspected, the history should focus on distinguishing Crohn’s disease from other bowel diseases. Alternative diagnoses include: infectious or ischemic colitis, irritable bowel syndrome, celiac disease, microscopic colitis, and ulcerative colitis. Although Crohn’s can be difficult to distinguish from ulcerative colitis, there are several components of the history which can make the diagnosis more apparent. Crohn’s is more likely to be associated with granulomas and intestinal strictures, therefore a history consistent with obstruction, such as nausea, colicky pain, and an abdominal mass, should increase suspicion for Crohn’s disease. In addition, since the lesions of Crohn’s are typically transmural and associated with fistulization, patients may describe rectal, perineal or even vaginal fistulas.

On the other hand, because of the preferential involvement of distal colon in ulcerative colitis, gross blood and mucous in the stool tends to be described more commonly in ulcerative colitis than in Crohn’s. Systemic symptoms such as fever and weight loss are occasionally seen in ulcerative colitis but more frequently seen in Crohn’s disease. Even in the most ideal of circumstances, the distinction between ulcerative colitis and Crohn’s disease may be impossible in 10-15% of cases, especially in the early stages of diagnosis. Such cases are termed indeterminate colitis.

Most estimates of Crohn’s disease in the United States are around 50-199 in 100,000 persons, contributing to the 1.3 million Americans affected by inflammatory bowel disease. Crohn’s follows a bimodal distribution for age of onset, with most patients developing the disease between the ages of 15-30 and 60-80. In general, women are between 1.1 and 1.8 times more likely to develop the disease than men.

Higher socioeconomic status and urban living has been associated with higher rates of disease. As a result, the number cases of both Crohn’s and ulcerative colitis have risen in the past century and are significantly higher in the United States than in the rest of the world. Changes in diet, antibiotic use, and the virtual eradication of intestinal helminthes in this country all have been proposed as explanations for the higher prevalence in this country.

Specifically, diets high in fatty foods and smoking have been implicated as factors that predispose patients to Crohn’s disease. Smoking has been well studied as it not only increases the risk of developing Crohn’s and progressing to more severe disease, but it also paradoxically protects against ulcerative colitis. No formal mechanism has been confirmed for this phenomenon although research is ongoing.

Genetics play a role in the development of Crohn’s disease, although not through typical genetic patterns. Several genes, such as IL23R, IRGM, and NOD2, have been implicated in the development of inflammatory bowel disease, most of which play a role in mucosal immunity. Significantly, the autophagy gene, known as ATG16L1, has been associated with Crohn’s disease but not with ulcerative colitis. Genetic testing remains limited to research, as it has not been proven to be of clinical benefit for diagnosis, management, or predicting disease severity.

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The most significant competing diagnoses are ulcerative colitis/indeterminate colitis. See above for a detailed discussion on distinguishing the two diagnoses.

Infectious colitis readily mimics the symptoms of inflammatory bowel disease. Microbiological causes include Campylobacter, Salmonella, Shigellosis, Clostridium difficile, Yersinia enterocolitis, and hemorrhagic variants of Escherichia coli. Typically diarrhea and abdominal symptoms associated with Crohn’s tend to follow a longer and more projected course than is seen in bacterial, infectious colitis. Parasitic infections can follow a more chronic course and should be suspected in an immunocompromised host or a patient returning from an endemic area.

Diverticulitis can often be confused with Crohn’s. Crohn’s is the more likely diagnosis when perianal disease or ileitis on small bowel series is seen. Similarly, mucosal abnormalities seen on endoscopy outside of the sigmoid and descending colon tend to point to the diagnosis of Crohn’s disease. Ischemic colitis can have transmural involvement much like Crohn’s disease, however, typically has a much more rapid and onset of symptoms than Crohn’s. An important competing diagnosis is microscopic colitis, both collagenous colitis and lymphocytic colitis. These present similarly to Crohn’s but have normal endoscopic appearance.

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The astute clinician will center the physical exam in a suspected Crohn’s patient on intestinal manifestations of the disease while looking for extra-intestinal signs of the disease. Inspection and palpation of the abdomen may reveal abdominal mass secondary to obstruction or granuloma formation. Bowel sounds may be hyperactive or even hypoactive as a result of this obstruction. The most common physical exam finding may be mild tenderness to palpation. Rectal, perineal and pelvic examination should be performed both to look for gross blood as well as to inspect for fistula formation.

Perineal examination is particularly important in the diagnosis of Crohn’s disease, as perineal manifestations of the disease are amongst the most devastating and debilitating. The perineum should be inspected for ulceration, fistulization and abscess formation.

Examination for extra-intestinal manifestations of Crohn’s disease should involve a thorough skin examination for erythema nodosum and pyoderma gangrenosum in addition to oral examination for aphthous ulcerations. Ocular inspection, visual acuity and ophthalmoscopic exam should be performed to investigate for episcleritis, uveitis, and iritis. Pulmonary auscultation may yield crackles suggestive of interstitial lung disease.

Common laboratory findings include mild anemia, mild leukocytosis, elevated C-reactive protein (CRP), and elevated erythrocyte sedimentation rate (ESR). The diagnostic approach to Crohn’s involves imaging studies (described below) which in turn guide endoscopy. A detailed review of endoscopic features of Crohn’s is beyond the scope of this chapter, however, in general endoscopy can reveal both gross and pathologic features consistent with this disease.

On gross endoscopic appearance, Crohn’s disease may manifest as ulcerations, diffuse inflammation, or exudate on the colonic wall. Crohn’s disease can be endoscopically differentiated from ulcerative colitis by the absence of continuous disease, by rectal sparing, and by the presence of “cobblestoning”, with areas of ulceration separated by narrow areas of healthy tissue. Pathologically, Crohn’s is diagnosed by the presence of granulomas on biopsy. However, these granulomas can be difficult to find, therefore the absence of granulomas on biopsy does not exclude the diagnosis.

Two serologic tests can play a role in differentiating Crohn’s disease and ulcerative colitis: the anti-S. cerevisiae antibody (ASCA) and the perinuclear antineutrophil cytoplasmic antibody (p-ANCA). ASCA is more often positive in Crohn’s disease while p-ANCA is more often positive in ulcerative colitis, therefore ASCA positivity and p-ANCA negativity suggests a diagnosis of Crohn’s disease. However, both these tests are nonspecific and should only be used as an adjunct to imaging and endoscopy.

Imaging studies play an important role in the initial diagnosis of Crohn’s disease as they can elucidate typical features of the disease, as well as guide future endoscopic investigations. Although many imaging modalities have been used, CT enterography has become the procedure of choice. CT is useful for demonstrating characteristic narrowing as well as the presence of abscesses, fistulas, and transmural thickening consistent with submucosal edema. Barium enema can increase the yield of diagnosis by aiding in the visualization of colonic lesions, although this procedure may not be well tolerated by every patient.

In the case of acute kidney injury or renal failure, when a contrast CT is not possible, an upper GI series with a small bowel follow through and spot films of the terminal ilium will yield a significant amount of information. This approach can be employed if CT enterography is initially unavailable or if repeat exams will likely be needed in order to decrease radiation exposure. It is important to note that patients with Crohn’s disease often need frequent imaging studies to re-evaluate disease status; therefore, being judicious with ionizing radiation studies is recommended.

Ultrasonography can be a useful adjunctive radiographic exam if tubo-ovarian pathology or biliary pathology is part of the differential as a cause of the presenting symptoms.

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In general, laboratory tests for Crohn’s are nonspecific and play a more significant role in the management of the disease rather than in the initial diagnosis. These include CRP, ESR, complete metabolic panel (CMP), and complete blood count (CBC). Their utility in assisting management will be covered below.

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The management of Crohn’s disease is centered on two objectives: managing acute flares of the disease and maintaining remission. If a patient is presenting with acute or worsening symptoms consistent with a flare, the immediate management involves treating the inflammation associated with the flare according to the severity of the flare.

In mild cases of Crohn’s, where the patient is able to ambulate and tolerate oral intake, the mainstay of therapy is salicylate therapy. Mesalamine at a dose of 3.2-4 grams per day as well as sulfasalazine at a dose of 3-6 grams per day are both effective.

There may be a modest benefit of antibiotics such as ciprofloxacin, metronidazole, and more recently rifaximin in the management of Crohn’s. The optimal regimen to include dose and duration has not been described. Metronidazole, either alone or in combination with ciprofloxacin, should particularly be considered in the management of uncomplicated fistulas associated with Crohn’s disease.

In moderate cases, where weight loss, abdominal pain, and vomiting are present, prednisone is the mainstay of therapy. Doses can be adjusted, but generally 40 mg daily should be taken until symptoms remit, usually for about 8-12 weeks. Steroids should not be used to maintain remission, and once symptoms are improved, the prednisone should be rapidly tapered.

In severe cases, particularly in the presence of high fever, guarding, or intractable vomiting, hospitalization and IV steroids should be used. The dose of IV steroids is 0.5-0.75 mg/kg/day. Usual regimens include methylprednisolone 40 mg daily or IV hydrocortisone 100 mg every 8 hours. Any patient with a severe flare should be admitted for inpatient management.

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The most important component of the daily physical exam is monitoring for signs of worsening flare. These include checking for fever, tachycardia, decreased mental status, and of course, any change in the abdominal exam. The abdominal exam should be geared towards identifying rebound tenderness, pain on palpation, and evidence of obstruction. The examiner should pay special attention to fever as it not only can signify flare, but also may be a sign of superimposed infection, which can be catastrophic in the setting of immunosuppressive agents.

The daily physical exam should monitor for side effects and complications of treatment. If salicylates are being used for mild disease, the physical exam should check for signs of gastrointestinal bleed/upset in addition to signs of progressive disease activity, as these agents often do not conclusively maintain remission of the disease. Infliximab is often associated with a mild infusion reaction. Fever should be monitored closely in all patients on immunosuppressants.

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CBC is an important laboratory parameter to monitor during inpatient management of Crohn’s disease both for changes in hemoglobin and leukocytes. Leukocytosis can be due to Crohn’s flare, superimposed infection, or as a response to therapy such as corticosteroids, and thus should be interpreted in the setting of the clinical course.

If there is fever and/or persistent diarrhea, labs to rule out bacterial colitis should be sent, to include stool leukocytes, fecal occult blood test, stool ova and parasites, stool cultures, and C. difficile toxin. This is essential both to differentiate superimposed bacterial colitis from Crohn’s flare as well as to rule out bacterial colitis prior to the initiation of immunosuppressive therapy.

CRP can be useful for monitoring response to therapy in patients in whom the initial CRP was elevated. Normalization of CRP while on therapy is evidence of favorable response to treatment, while persistently elevated CRP indicates higher likelihood of clinical relapse.

Markers of nutritional status, ESR, and B12 levels should be deferred to the outpatient setting.

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Treatment options can be inconsistent, largely due to the varied course that the disease may take and the lack of data on long-term management of disease. In general a stepwise approach has been developed that is centered on the severity of the exacerbation. For mild disease, salicylates and antibiotics are the mainstay of therapy. Once control of flare is achieved, mesalamine is used long-term to induce remission.

In the case of long moderate to severe disease, oral and intravenous steroids are used to treat acute disease. If flare continues despite corticosteroid therapy, there may be a role for infliximab, although relapses do occur after the agent is discontinued. Once the flare is controlled, long-term therapy usually involves immunosuppressant therapy. In moderate to severe cases, recent trials have shown that the efficacy of other monoclonal antibody therapies, such as ustekinumab, secukinumab, and vedolizumab, have been associated with a decreased rate of relapse.

Current guidelines note that novel end points for successful medical therapy including outcome and prognostic factors have yet to be definitively established.

The main pitfall in management is improper treatment of pain. Many providers use narcotics for pain management, even though Crohn’s disease patients treated with narcotics have been shown to have worse disease activity and diminished quality of life. When possible, pain associated with Crohn’s disease should be managed with non-narcotic alternatives.

There also exists controversy about the ideal management strategy for long-term Crohn’s exacerbations. Some experts advocate a “bottom-up” strategy where therapy is initiated slowly and increases over time, while others adopt a “top-down” approach, employing the strongest agents initially (usually infliximab) and stepping down therapy over time. These management decisions should be made in consultation with an experienced gastroenterologist.

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Mesalamine and sulfasalazine are both contraindicated in severe renal failure. Use of mercaptopurine and methotrexate is cautioned, and doses of these agents should be decreased in the case of severe renal impairment.

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Alcohol should be avoided with methotrexate as this increases the risk of hepatotoxicity. Folic acid can reduce the risk of liver toxicity. Infliximab has been linked to acute liver injury in addition to reactivation of hepatitis B.

There is caution for infliximab in the case of moderate to severe heart failure.

No change in standard management.

Methotrexate should be avoided in any female who has any possibility of becoming pregnant.

No change in standard management.

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Rule-out of concomitant infection, especially hepatitis and tuberculosis, is essential prior to initiation of infliximab therapy.

Caution for infliximab in the case of moderate to severe COPD.

If there is intractable nausea or vomiting oral steroids should be replaced with intravenous steroids.

No change in standard management.

Chronic pain is often seen concomitantly with Crohn’s disease. When possible this should be managed with non-narcotic medications. Additionally, experts have long since associated psychological variables with Crohn’s disease. One prospective study found that Beck Depression Inventory scores were independently associated with disease activity and that anxiety, hopelessness, and recent life changes were suggestive of higher disease activity. There is evidence that managing anxiety can improve outcomes in the management of Crohn’s disease.

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Appropriate sign-out should be given for management of pain. Covering physicians should avoid narcotics if possible. Tramadol often is the drug of choice. Sign-out should also mention that pain may be a sign of worsening disease, in which case the intervention may involve increasing the steroid dose.

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The average length of stay for hospitalizations due to Crohn’s disease is around 9 days.

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Ideally a patient is ready for discharge when pain and symptoms are controlled, fever has remitted, there is evidence of remission, and there is ability to tolerate PO.

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Follow-up with gastroenterology should be arranged for 2-4 weeks after discharge.

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If there is anticipation of initiation of biologic agents as an outpatient, a hepatitis panel can be ordered and PPD can be placed while the patient is still on inpatient status.

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A CBC and CRP can be ordered prior to first clinic visit. Both ESR and CRP can be used, but in general, most gastroenterologists prefer CRP.

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Unless there are concomitant medical problems, patients can be discharged to home with outpatient follow-up.

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The prognosis for Crohn’s is generally good, with 1 year survival rates of around 94%. Disease severity significantly impacts patient survival; however, most Crohn’s disease survival studies to date are prior to modern biologic therapies. Patients should be counseled that the duration of illness affects the risk of death and complications as well as the efficacy of therapy.

Malignancy is often associated with prolonged Crohn’s disease, to include colorectal and intestinal adenocarcinomas, lymphomas, and squamous cell carcinoma around chronic fistulas. Despite an expanding body of evidence demonstrating the association of cancer with longstanding Crohn’s disease, specific surveillance guidelines have not yet been defined.

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None.

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In the absence of clinical bleeding, DVT prophylaxis should be ordered on patients admitted with exacerbations of Crohn’s disease. Sequential compression devices can be used in the case of active bleeding.

When feasible, the care of patients with Crohn’s should include enlisting a multidisciplinary team designed to integrate specialist input with patient education and support.

Lichtenstein, Gary R.. “Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT™ registry”. The American journal of gastroenterology. vol. 107. 2012. pp. 1409-1422.